Intuniv 2 MG 24 HR Extended Release Oral Tablet
DRUG INTERACTIONS
7 Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 1).
Dose adjustments are recommended .
Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 2).
Therefore, no dose adjustments in methylphenidate or lisdexamfetamine are necessary.
[ ] see Dosage and Administration (2.7) Figure 1: Impact of Other Drugs on the Pharmacokinetics (PK) of Intuniv Figure 2: Impact of Intuniv on the Pharmacokinetics (PK) of Other Drugs Strong CYP3A4 inhibitors (e.g., ketoconazole): Coadministration increases guanfacine exposure.
Guanfacine dose should be limited to no more than 2 mg/day.
When discontinuing CYP3A4 inhibitors, guanfacine dose should be doubled based on patient tolerability.
The maximum dose should not exceed 4 mg/day ( and ).
2.7 7 Strong CYP3A4 inducers (e.g., rifampin): Coadministration decreases guanfacine exposure.
Guanfacine dose may be titrated up to 8 mg/day.
When discontinuing CYP3A4 inducers, guanfacine dose should be decreased by half in 1-2 weeks based on patient tolerability.
The maximum dose should not exceed 4 mg/day ( and ).
2.7 7 Figure 1 Figure 2
OVERDOSAGE
10 Symptoms Post-marketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose.
Initial hypertension may develop early and may be followed by hypotension.
Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center’s National Poison Data System.
Miosis of the pupils may be noted on examination No fatal overdoses of guanfacine have been reported in published literature.
.
Treatment Consult a Certified Poison Control Center by calling 1-800-222-1222 for up to date guidance and advice.
Management of INTUNIV overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression.
Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension.
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DESCRIPTION
11 INTUNIV is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only.
The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride.
The molecular formula is C H Cl N O·HCl corresponding to a molecular weight of 282.55.
The chemical structure is: ® 9 9 2 3 Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone.
The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL).
Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base.
The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate.
In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763.
spd503-chemical-stucture
CLINICAL STUDIES
14 14.1 Safety and Efficacy Studies The efficacy of INTUNIV in the treatment of ADHD was established in 3 placebo-controlled monotherapy trials (Studies 1, 2, and 4) and in 1 placebo-controlled adjunctive trial with psychostimulants (Study 3) in pediatric population.
Studies 1, 2, and 3 were conducted in children and adolescents ages 6-17 and Study 4 was conducted in children ages 6-12 years.
® Studies 1 and 2: Fixed-dose INTUNIV Monotherapy ® Study 1 was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345).
Study 2 was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324).
In both studies, randomized subjects in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started The lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs).
Patients who weighed less than 25 kg (55 lbs) were not included in either study.
® ® Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales.
The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores.
Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2).
The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo for Studies 1 and 2.
Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV randomized treatment groups in both studies, as well as the 1 mg INTUNIV treatment group (for patients 55-110 lbs) that was included only in Study 2 (see Table 6).
® ® ® Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis.
When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day.
Doses up to 0.12 mg/kg/day were shown to provide additional benefit.
Controlled, monotherapy long-term efficacy studies (>9 weeks) have not been conducted.
In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs.
13-17).
Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender.
Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup.
Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the adolescent patients.
In these studies, patients were randomized to a fixed dose of INTUNIV rather than optimized by body weight.
Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients.
Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg.
In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations.
® Table 6: Fixed dose Studies Study (Age Range) Primary Efficacy Measure Treatment Group Placebo Intuniv ® 1mg Intuniv ® 2mg Intuniv ® 3mg Intuniv ® 4mg (6 – 17 years) 1 Mean Baseline (SD) 38.1 (9.34) — 36.1 (9.99) 36.8 (8.72) 38.4 (9.21) LS Mean Change from Baseline (SE) -8.5 (1.42) — -15.9 (1.37) -16.0 (1.38) -18.5 (1.39) LS Mean Difference from Placebo (95% CI) — — -7.4 (-11.3, -3.5) a -7.5 (-11.4, -3.6) a -10.0 (-13.9, -6.1) a (6 – 17 years) 2 Mean Baseline (SD) 39.3 (8.85) 41.7 (7.81) 39.9 (8.74) 39.1 (9.22) 40.6 (8.57) LS Mean Change from Baseline (SE) -12.7 (1.60) -19.4 (1.69) -18.1 (1.60) -20.0 (1.64) -20.6 (1.60) LS Mean Difference from Placebo (95% CI) — -6.8 (-11.3, -2.2) a -5.4 (-9.9, -0.9) a -7.3 (-11.8, -2.8) a -7.9 (-12.3, -3.4) a LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) Doses were shown to be statistically significantly superior to placebo.
a Study 3: Flexible-dose INTUNIV as Adjunctive Therapy to Psychostimulants ® Study 3 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV (1mg, 2mg, 3mg and 4mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455).
Subjects were started at the 1 mg INTUNIV dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV dose not to exceed 4 mg/day based on tolerability and clinical response.
The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering.
Subjects took INTUNIV either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning.
Allowable psychostimulants in the study were ADDERALL XR , VYVANSE , CONCERTA , FOCALIN XR , RITALIN LA , METADATE CD or FDA-approved generic equivalents.
® ® ® ® ® ® ® ® ® ® Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales.
The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores.
Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8).
Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV dosing (see Table 7).
Nearly two-thirds (64.2%) of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range.
® ® Study 4: Flexible-dose INTUNIV Monotherapy ® Study 4 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6-12 years (n=340).
® Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales.
The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores.
Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8).
Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo in both AM and PM dosing groups of INTUNIV (see Table 7).
® ® Table 7: Flexible-Dose studies Study (Age Range) Treatment Group Placebo Intuniv ® 1mg – 4mg AM PM (6 – 17 years) 3 a Mean Baseline (SD) 37.7 (7.75) 37.6 (8.13) 37.0 (7.65) LS Mean Change from Baseline (SE) -15.9 (0.96) -20.3 (0.97) -21.2 (0.97) LS Mean Difference from Placebo (95% CI) — -4.5 (-7.5, -1.4) b -5.3 (-8.3, -2.3) b (6 – 12 years) 4 Mean Baseline (SD) 42.9 (6.21) 41.7 (6.39) 41.6 (6.66) LS Mean Change from Baseline (SE) -10.6 (1.20) -20.0 (1.23) -20.4 (1.19) LS Mean Difference from Placebo (95% CI) — -9.4 (-12.8, -6.0) b -9.8 (-13.1, -6.4) b LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) Treatment was given in combination with a psychostimulant.
Doses were shown to be statistically significantly superior to placebo.
a b
HOW SUPPLIED
16 /STORAGE AND HANDLING NDC:64725-0515-1 in a CONTAINER of 30 TABLET, EXTENDED RELEASES
RECENT MAJOR CHANGES
Dosage and Administration, Dose Selection ( ), 02/2013 2.2
GERIATRIC USE
8.5 Geriatric Use The safety and efficacy of INTUNIV in geriatric patients have not been established.
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DOSAGE FORMS AND STRENGTHS
3 1 mg, 2 mg, 3 mg and 4 mg extended-release tablets Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg ( ) 3
MECHANISM OF ACTION
12.1 Mechanism of Action Guanfacine is a central alpha -adrenergic receptor agonist.
Guanfacine is not a central nervous system (CNS) stimulant.
The mechanism of action of guanfacine in ADHD is not known.
2A
INDICATIONS AND USAGE
1 INTUNIV is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications.
The efficacy of INTUNIV was studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration) and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV criteria for ADHD [ ].
The effectiveness of INTUNIV for longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials.
® ® ® see Clinical Studies (14) ® INTUNIV is a central alpha -adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications ( ).
® 2A 1
PEDIATRIC USE
8.4 Pediatric Use Safety and efficacy of INTUNIV in pediatric patients less than 6 years of age have not been established.
® Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2-3 times the maximum recommended human dose (MRHD).
Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD.
In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day.
The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m basis.
The effects on fertility were not evaluated in this study.
2 In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate.
The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m basis.
These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day.
2
PREGNANCY
8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of INTUNIV in pregnant women.
No fetal harm was observed in rats and rabbits with administration of guanfacine at 6 and 4 times, respectively, the maximum recommended human dose.
Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta.
However, administration of guanfacine to rats and rabbits at 6 and 4 times, respectively, the maximum recommended human dose of 4 mg/day on a mg/m basis resulted in no evidence of harm to the fetus.
Higher doses (20 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity.
2
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk.
Because many drugs are excreted in human milk, caution should be exercised when INTUNIV is administered to a nursing woman.
Observe human milk-fed infants for sedation and somnolence.
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WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hypotension, bradycardia, and syncope: Use INTUNIV with caution in patients at risk for hypotension, bradycardia, heart block, or syncope (e.g., those taking antihypertensives).
Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy.
Advise patients to avoid becoming dehydrated or overheated ( ).
® 5.1 Sedation and somnolence: Occur commonly with INTUNIV .
Consider the potential for additive sedative effects with CNS depressant drugs.
Caution patients against operating heavy equipment or driving until they know how they respond to INTUNIV ( ).
® ® 5.2 5.1 Hypotension, Bradycardia, and Syncope Treatment with INTUNIV can cause dose-dependent decreases in blood pressure and heart rate.
Decreases were less pronounced over time of treatment.
Orthostatic hypotension and syncope have been reported .
® [ ] see Adverse Reactions (6.1) Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy.
Use INTUNIV with caution in patients with a history of hypotension, heart block, bradycardia, cardiovascular disease, or who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration.
Use INTUNIV with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope.
Advise patients to avoid becoming dehydrated or overheated.
® ® 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [ .
Before using INTUNIV with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects.
Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV Advise patients to avoid use with alcohol.
] see Adverse Reactions (6.1) ® ® .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information ) Dosing and Administration Instruct patients to swallow INTUNIV whole with water, milk or other liquid.
Patients should not take INTUNIV together with a high-fat meal, since this can raise blood levels of INTUNIV .
Instruct the parent or caregiver to supervise the child or adolescent taking INTUNIV and to keep the bottle of tablets out of reach of children.
® Tablets should not be crushed, chewed or broken prior to administration because this may increase the rate of release of the active drug .
® ® ® Instruct patients on how to properly taper the medication, if the physician decides to discontinue treatment.
[ ].
see Dosage and Administration (2.5) Adverse Reactions Advise patients that sedation can occur, particularly early in treatment or with dose increases.
Caution against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV Headache and abdominal pain can also occur.
If any of these symptoms persist, or other symptoms occur, the patient should be advised to discuss the symptoms with the physician.
® [ ].
see Warnings and Precautions (5.2) Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope Advise patients to avoid use with alcohol.
[ ].
see Warnings and Precautions (5.1)
DOSAGE AND ADMINISTRATION
2 Recommended dose: 1 to 4 mg once daily in the morning or evening ( ).
2.2 Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week ( ).
2.2 Do not crush, chew or break tablets before swallowing ( ).
2.1 Do not administer with high-fat meals, because of increased exposure ( ).
2.1 Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles ( ).
2.3 If switching from immediate-release guanfacine, discontinue that treatment and titrate with INTUNIV as directed ( ).
® 2.3 Consider dosing on a mg/kg basis.
Improvements observed starting at doses of 0.05-0.08 mg/kg once daily.
Doses up to 0.12 mg/kg once daily may provide additional benefit ( ).
2.2 When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days ( ).
2.5 2.1 General Instruction for Use Do not administer with high fat meals, due to increased exposure.
Swallow tablets whole.
Do not crush, chew, or break tablets because this will increase the rate of guanfacine release.
2.2 Dose Selection INTUNIV should be taken once daily, either in the morning or evening, at approximately same time each day.
Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week.
Maintain the dose within the range of 1 mg to 4 mg once daily, depending on clinical response and tolerability, for both monotherapy and adjunctive therapy to a psychostimulant.
Doses above 4 mg/day have not been systematically studied in controlled clinical studies .
[ ] see Clinical Studies (14.1) Clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg once daily in both mono- and adjunctive therapy.
Efficacy increased with increasing weight-adjusted dose (mg/kg).
If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit.
In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events).
Thus, consideration should be given to dosing INTUNIV on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment.
® 2.3 Switching from Immediate-Release Guanfacine to INTUNIV If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV following above recommended schedule.
® Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles.
INTUNIV has a delayed T , reduced C and lower bioavailability compared to those of the same dose of immediate-release guanfacine .
® max max [ ] see Clinical Pharmacology (12.3) 2.4 Maintenance Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for an extended period.
The effectiveness of INTUNIV for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials.
Therefore the physician electing to use INTUNIV for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
® ® 2.5 Discontinuation Infrequent, transient elevations in blood pressure above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of guanfacine.
To minimize these effects, the dose should generally be tapered in decrements of no more than 1 mg every 3 to 7 days.
2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, physicians should consider titration based on patient tolerability.
2.7 Dose Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or Inducers Dosage adjustments for INTUNIV are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole), or CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St.John’s wort) (Table 1) .
® [ ] see Drug Interactions (7) Table 1: Dose Adjustments in Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Comedications Scenarios Initiate INTUNIV when taking comedications ® Continue INTUNIV when adding a comedication ® Stop a comedication when continuing INTUNIV ® Strong CYP3A4 Inhibitors INTUNIV dose should be limited to 2 mg/day ® INTUNIV dose should be decreased by half.
® INTUNIV dose should be doubled based on patient tolerability.
The maximum dose should not exceed 4 mg/day ® Strong CYP3A4 Inducers INTUNIV dose may be titrated up to 8 mg/day.
Consider faster titration (e.g.
in increments of 2 mg/week) ® Consider increase INTUNIV dose gradually in 1-2 weeks to 2 fold of the original dose based on patient tolerability.
® INTUNIV dose should be decreased by half in 1-2 weeks based on patient tolerability.
The maximum dose should not exceed 4 mg/day ®